Depression is identified among the leading global causes of disability by the World Health Organization, and affects 15-20% of individuals during their lifetime. All approved antidepressants require 2 - 4 weeks of treatment for their therapeutic effects to emerge, and 30-40% of depressed subjects do not respond adequately to current treatments. Fast-onset antidepressants with novel mechanisms of action are greatly needed. Few pharmacological agents have been identified which induce rapid antidepressant effects. None of these, including the noncompetitive NMDA antagonist ketamine, are approved for clinical use due to adverse side effects. We recently found that selective serotonin 2C (5-HT2C) receptor antagonists produce substantially faster-onset antidepressant effects than serotonin reuptake inhibitors using mouse models of chronic antidepressant action. This project proposes to identify the mechanisms underlying the rapid-onset antidepressant effects of 5-HT2C antagonists using mice. We already found that short-term treatment with 5- HT2C antagonists induces CREB phosphorylation, BDNF expression, and neuronal remodeling in the medial prefrontal cortex. We propose to use an integrated and multidisciplinary approach to further delineate these mechanisms which includes behavioral, molecular genetic, biochemical, morphological, and pharmacological approaches. Specific Aim 1 will identify the mechanisms by which 5-HT2C antagonist treatment induces BDNF expression. We will examine the role of 5-HT2C receptor blockade on pyramidal vs. GABAergic interneurons in the mPFC. We will also examine the role of the dopaminergic system, and will identify the specific dopamine receptor monomer and heteromers mediating this effect. Specific Aim 2 will determine which signaling molecules downstream of BDNF induce neuronal remodeling and the antidepressant behavioral response. We will assess whether 5-HT2C antagonists and ketamine utilize the same signaling cascade downstream of BDNF to induce rapid antidepressant effects. This work could provide evidence required to justify human studies examining selective 5-HT2C antagonists as potential fast-onset antidepressants. Importantly, this work could also identify novel targets for which new fast-onset antidepressants could be developed. Given the dearth of knowledge regarding the neural mechanisms underlying fast-onset antidepressant effects, these studies could provide critical insights into this phenomenon. In summary, the proposed work will provide valuable new insights into the mechanisms underlying fast-onset antidepressant action and lead to novel treatments.